Systemic Lupus Erythematosis is a systemic autoimmune disease of unknown cause characterized by the production of antibodies directed against a variety of self antigens. A spontaneous form of lupus which closely parallels the human disease also occurs in the lupus-prone B/W mouse. Production of autoantibodies in humans and the B/W mouse is dependent on activated CD4+ helper T cells. Activation of these T-cells requires interactions between the T-cell antigen receptor and antigen presented by an antigen-presenting cell, as well as a second signal which can be provided by interactions between B7 molecules on antigen- presenting cells and the CD28 molecule on the T-cell. Blockade of the first signal by antibodies against the CD4 molecule is effective in preventing or reversing lupus in the B/W mouse, an observation which in part led to therapeutic trials with anti-CD4 antibodies in humans with autoimmune disease. Blockade of the second activation signal by a soluble molecule called aLA4Ig has recently been shown to dramatically slow the progression of lupus in B/W mice as well as treat established disease. The mechanism of this effect, however, is unknown. T cell costimulation can also be provided by interactions between CD4O and its cognate ligand gp39, but the role of these molecules in autoimmunity is also unknown. The objective of the current proposal is to further define the mechanism by which interruption of T-cell costimulation can block the development of autoimmunity. This objective encompasses five specific aims: Specific Aim 1. To determine the relative contributions of B7-1 and B7-2 to the development of autoimmunity in lupus-prone NZB/NZW (B/W) mice. Specific Aim 2. To determine if blockade of CD28 and/or CTLA4 early in life can induce tolerance to autoantigens. Specific Aim 3. To determine the effects of costimulation blockade on T cell cytokine production in lupus-prone mice Specific Aim 4. To determine the role of Th1 and Th2 cells in the development and maintenance of murine lupus. Specific Aim 5. To determine whether interruption of multiple costimulation signals can have a synergistic effect on murine lupus. These studies will not only define the critical costimulation signal(s) necessary for the development of murine lupus, but should point to new, more specific therapeutic approaches in humans.